CN101801416A - Sealmess capsule - Google Patents
Sealmess capsule Download PDFInfo
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- CN101801416A CN101801416A CN200880105165A CN200880105165A CN101801416A CN 101801416 A CN101801416 A CN 101801416A CN 200880105165 A CN200880105165 A CN 200880105165A CN 200880105165 A CN200880105165 A CN 200880105165A CN 101801416 A CN101801416 A CN 101801416A
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- capsule
- temperature
- shell
- sealmess
- interfacial tension
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4833—Encapsulating processes; Filling of capsules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
- Y10T428/2984—Microcapsule with fluid core [includes liposome]
Abstract
Disclosed is a seamless capsule which can be produced without using any interfacial tension regulator or gelation accelerator. Specifically disclosed is a seamless capsule comprising: a shell formed by a shell composition comprising a gelatin and a plasticizer and containing no interfacial tension regulator or gelation accelerator; and a capsule content containing no interfacial tension regulator or gelation accelerator.
Description
Technical field
The Sealmess capsule that the present invention relates to comprise shell (epithelium) and capsule 's content with and preparation method thereof, described shell (epithelium) is formed by shell (epithelium) compositions, described shell compositions contains gelatin and plasticizer and does not contain the interfacial tension regulator and gelation promoter, and described capsule 's content does not contain interfacial tension regulator or gelation promoter.In addition, the present invention relates to following Sealmess capsule, its thickness has minimum inhomogeneities, and it does not steep eye or minimum bubble eye is only arranged, have the shell that is formed by the shell compositions, this shell compositions contains gelatin and plasticizer and does not contain the interfacial tension regulator or gelation promoter.
Background technology
Encapsulated technology is widely used in fields such as drug products, food, similar medicine usually.In these capsules, Sealmess capsule is based on the encapsulation techniques of the gelling characteristic of tension force that utilizes oil-water interface to produce and conchiolin.Although Sealmess capsule is a kind of of soft capsule, be extensive use of because of its following feature in recent years, as wide etc. to the range of choice of the thickness of particle size, film, capsule and hardness and capsule dissolution time.
As the material that is used to form this capsular formation shell (epithelium) (shell (epithelium) compositions), use dissolubility in the body excellent and can discharge the material of content by quick disintegrate.The representative instance of this material comprises that gelatin forms material with comprising the compositions of gelatin.Usually, Sealmess capsule is by following preparation, it (for example uses interfacial tension regulator or gelation promoter, oils and fats, phospholipid, polar organic solvent such as ethanol etc.) be added in shell compositions and/or the capsule 's content, has high-quality Sealmess capsule with preparation, the bubble eye of this Sealmess capsule (defective of the cavity shape that produces in the shell) is little, and the less inhomogeneities (thickness of the shell significantly changes at capsular different parts) of its thickness demonstration, etc.
Patent documentation 1 has been described the pharmaceutical composition of treatment or angiocardiopathy preventing, and it comprises the omega 3-fatty acid that ratio is at least the 80wt% of total fatty acids, and (all-Z)-5,8,11,14,17-eicosapentaenoic acid (EPA) C20:5 and (all-Z)-4,7,10,13,16,19-docosahexenoic acid (DHA) C22:6 is to exist in 1: 2 to 2: 1 with relative quantity, and accounts for the 80wt% at least of total fatty acids.Particularly, described EPA ethyl ester capsule, DHA ethyl ester capsule, d-alpha tocopherol capsule, gelatine capsule, glycerol capsule, iron oxide red capsule and iron oxide yellow capsule, and described Perle (1g/l capsule) as preparation embodiment.These raw materials use standard encapsulation machine to be filled in the avette Perle (size 20).
Patent documentation 2 has been described the preparation method of Sealmess capsule, this method has following steps: prepare to have into the outer side nozzle of circular concentric setting and the combining nozzle device of interior side nozzle, shell material is provided and provides packing material to above-mentioned outside nozzle to above-mentioned inboard nozzle, above-mentioned shell material is extruded above-mentioned outer side nozzle and simultaneously above-mentioned packing material is extruded above-mentioned interior side nozzle, wherein the above-mentioned shell material by said nozzle has and the identical circulation of above-mentioned packing material by side nozzle in above-mentioned, shell material parcel packing material in this Sealmess capsule.
Patent documentation 3 has been described the preparation method of Sealmess capsule, comprises by droplet is contacted with solidified liquid being cured to the most external of drop when young, and wherein above-mentioned drop passes through to the above-mentioned solidified liquid of small part with the corkscrew motion drippage.
Above-mentioned prior art is not described the bubble eye that suppresses in the shell and the formation of uneven gauge, does not describe this inhibitory action yet and uses relation between interfacial tension regulator and the gelation promoter.Be its stabilisation of not describing the capsule 's content sealed in the capsule such as ingredient etc. with should be specifically noted that, and the amount that increases capsule 's content (for example, ingredient).
Yet use interfacial tension regulator and gelation promoter influence the stability of capsule 's content (as the ingredient of enclosing) etc. unfriendly, or prevent that the amount of capsule 's content (for example, ingredient) from increasing (the capsular content of per unit increases).
Patent documentation 1: No. 2810916 communiques of Japan Patent
Patent documentation 2: the flat 10-506841 communique of special table
Patent documentation 3: No. 3159724 communiques of Japan Patent
Summary of the invention
The problem to be solved in the present invention
The object of the invention provide capsule 's content excellent in stability Sealmess capsule with and preparation method thereof, it allows high-load capsule 's content, and not contain bubble eye or have also be the Sealmess capsule of minimum bubble eye even provide, and the thickness of this Sealmess capsule has minimum inhomogeneities.
The means of dealing with problems
The present inventor has carried out various researchs to the constituent of shell compositions and capsule 's content and the condition of Sealmess capsule preparation, found to comprise the Sealmess capsule of shell and capsule 's content, the problems referred to above have been solved, and set up its preparation method, thereby finished the present invention, described shell is formed by the shell compositions, and described shell compositions contains gelatin and plasticizer and do not contain the interfacial tension regulator or gelation promoter, and described capsule 's content does not contain interfacial tension regulator or gelation promoter.
The present invention's description specific as follows.
[1] Sealmess capsule, it comprises shell and capsule 's content, described shell is formed by the shell compositions, and described shell compositions contains gelatin and plasticizer and do not contain the interfacial tension regulator or gelation promoter, and described capsule 's content does not contain interfacial tension regulator or gelation promoter.
[2] [1] described Sealmess capsule, the gel strength of wherein said gelatin is 200-300g.
[3] [1] or [2] described Sealmess capsule, the viscosity of wherein said gelatin is 2-6mPas.
[4] each described Sealmess capsule of [1]-[3], wherein said gelatin is from Corii Sus domestica.
[5] [1] described Sealmess capsule, wherein this plasticizer is a glycerol.
[6] [1] described Sealmess capsule, wherein this plasticizer is a sorbitol.
[7] [1] described Sealmess capsule, wherein this plasticizer is the mixture of glycerol and sorbitol.
[8] [7] described Sealmess capsule, wherein the weight ratio of glycerol and sorbitol is 1: 5-5: 1.
[9] [1] described Sealmess capsule, wherein the weight ratio of gelatin and plasticizer is 10: 1-1: 1.
[10] [1] described Sealmess capsule, wherein said capsule 's content is the active constituents of medicine compositions.
[11] [10] described Sealmess capsule, wherein said capsule 's content are included in the active constituents of medicine compositions that near 25 ℃ temperature had low or too high interfacial tension.
[12] [10] described Sealmess capsule, wherein said active constituents of medicine compositions comprises the omega 3-fatty acid Arrcostab.
[13] [12] described Sealmess capsule, wherein said active constituents of medicine compositions comprises the omega 3-fatty acid Arrcostab of the ratio that is not less than 90%w/w.
[14] [13] described Sealmess capsule, wherein said active constituents of medicine compositions comprise EPA ethyl ester (EPA-E) and DHA ethyl ester (docosahexaenoic acid ethyl), and the toatl proportion of these two kinds of compositions is not less than 80%w/w.
[15] [14] described Sealmess capsule, wherein said active constituents of medicine compositions comprise the EPA ethyl ester that is not less than 40%w/w and are not less than the DHA ethyl ester of 34%w/w.
[16] [15] described Sealmess capsule, wherein said active constituents of medicine compositions comprise the Ω-3-acetoacetic ester 90 that meets European Pharmacopoeia.
[17] [10] described Sealmess capsule, wherein the weight ratio of active constituents of medicine compositions and " summation of gelatin and plasticizer " is 10: 1-1: 10.
[18] [1] described Sealmess capsule, the weight ratio of its mesochite and capsule 's content is 10: 1-1: 10.
[19] method of the Sealmess capsule of preparation claim 1, this method is a dropping preparation method in the liquid, be included near the multiple nozzle of the employed device of dropping preparation method the temperature of control " capsule 's content that does not contain interfacial tension regulator or gelation promoter ", the temperature of " by containing gelatin and plasticizer and not containing the interfacial tension regulator or shell composition solution that the shell compositions of gelation promoter forms " and the temperature of " carrier fluid ".
[20] [19] described preparation method, wherein the temperature of " capsule 's content that does not contain interfacial tension regulator or gelation promoter " is controlled between setting value ± 2 ℃, and this temperature is in 5 ℃ of-25 ℃ of scopes.
[21] [19] described preparation method, wherein the temperature of " by containing gelatin and plasticizer and not containing the interfacial tension regulator or shell composition solution that the shell compositions of gelation promoter forms " is controlled between setting value ± 2 ℃, and this temperature is in 50 ℃ of-80 ℃ of scopes.
[22] [19] described method, wherein the temperature of " carrier fluid " is controlled between setting value ± 1 ℃, and this temperature is in 1 ℃ of-15 ℃ of scope.
[23] [19] described preparation method, wherein the difference of the temperature of the temperature of " capsule 's content that does not contain interfacial tension regulator or gelation promoter " and " by containing gelatin and plasticizer and not containing the interfacial tension regulator or shell composition solution that the shell compositions of gelation promoter forms " is not less than 25 ℃ and be not more than 75 ℃.
[24] [19] described preparation method, wherein the difference of the temperature of the temperature of " by containing gelatin and plasticizer and not containing the interfacial tension regulator or shell composition solution that the shell compositions of gelation promoter forms " and " carrier fluid " is not less than 35 ℃ and be not more than 79 ℃.
[25] Sealmess capsule, it is by dropping preparation method preparation in the liquid, this method is included near the multiple nozzle of the employed device of dropping preparation method, the temperature of control " capsule 's content that does not contain interfacial tension regulator or gelation promoter ", the temperature of " by containing gelatin and plasticizer and not containing the interfacial tension regulator or shell composition solution that the shell compositions of gelation promoter forms " and the temperature of " carrier fluid ".
[26] [25] described Sealmess capsule, wherein said temperature is controlled at following temperature:
The temperature of " capsule 's content " is controlled between setting value ± 2 ℃, and this temperature is in 5 ℃ of-25 ℃ of scopes;
The temperature of " shell composition solution " is controlled between setting value ± 2 ℃, and this temperature is in 50 ℃ of-80 ℃ of scopes;
The temperature of " carrier fluid " is controlled between setting value ± 1 ℃, and this temperature is in 1 ℃ of-15 ℃ of scope;
The difference of the temperature of the temperature of " capsule 's content " and " shell composition solution " is not less than 25 ℃ and be not more than 75 ℃; With
The difference of the temperature of " shell composition solution " and the temperature of " carrier fluid " is not less than 35 ℃ and be not more than 79 ℃.
[27] [25] described Sealmess capsule, wherein said temperature is controlled at following temperature:
The temperature of " capsule 's content " is controlled between setting value ± 1 ℃, and this temperature is in 12 ℃ of-22 ℃ of scopes;
The temperature of " shell composition solution " is controlled between setting value ± 1 ℃, and this temperature is in 60 ℃ of-70 ℃ of scopes;
The temperature of " carrier fluid " is controlled between setting value ± 0.5 ℃, and this temperature is in 3 ℃ of-11 ℃ of scopes;
The difference of the temperature of the temperature of " capsule 's content " and " shell composition solution " is not less than 38 ℃ and be not more than 58 ℃; With
The difference of the temperature of " shell composition solution " and the temperature of " carrier fluid " is not less than 49 ℃ and be not more than 67 ℃.
[28] Sealmess capsule, it has the shell that is formed by the shell compositions, and this shell compositions contains gelatin and plasticizer and does not contain the interfacial tension regulator or gelation promoter, and the ratio of the minimum thickness/maximum ga(u)ge of the shell after just encapsulated is not less than 0.6.
[28a] Sealmess capsule, it has the shell that is formed by the shell compositions, and this shell compositions contains gelatin and plasticizer and does not contain the interfacial tension regulator or gelation promoter, and the ratio of the minimum thickness/maximum ga(u)ge of described shell is not less than 0.6.
[29] [28] described Sealmess capsule, it has the capsule 's content that does not contain interfacial tension regulator or gelation promoter.
[30] Sealmess capsule, it has the shell that is formed by the shell compositions, and this shell compositions contains gelatin and plasticizer and does not contain the interfacial tension regulator or gelation promoter, does not have the bubble eye in the described shell.
[31] [30] described Sealmess capsule, it has the capsule 's content that does not contain interfacial tension regulator or gelation promoter.
[32] Sealmess capsule, it has the shell that is formed by the shell compositions, this shell compositions contains gelatin and plasticizer and does not contain the interfacial tension regulator or gelation promoter, in encapsulated back and before drying, the diameter of the bubble eye of shell is below 1/2 of average thickness of shell.
[33] [32] described Sealmess capsule, it has the capsule 's content that does not contain interfacial tension regulator or gelation promoter.
[34] Sealmess capsule, it has the shell that is formed by the shell compositions, this shell compositions contains gelatin and plasticizer and does not contain the interfacial tension regulator or gelation promoter, in encapsulated back and at dry before measurement regularly, does not exist diameter to surpass 1/2 bubble eye of the average thickness of shell.
[35] [34] described Sealmess capsule, it has the capsule 's content that does not contain interfacial tension regulator or gelation promoter.
The invention effect
Because Sealmess capsule of the present invention does not contain interfacial tension regulator or gelation promoter,, and allow high-load capsule 's content so it has the stability of excellent capsule 's content.And, even can providing not contain the bubble eye or exist, the present invention also only is the high-quality Sealmess capsule of minimum bubble eye, its thickness shows minimum inhomogeneities.
Because content can be very high, the unit sizes of preparation can minimize, thereby can realize highly being easy to utilizing in administration and the storage process less space.And, can improve the stability in the storage process, thus expanded service life.
The accompanying drawing summary
[Fig. 1] Sealmess capsule of the present invention.
Detailed Description Of The Invention
The present invention following by explaining in detail with reference to instantiation.
(composition of shell composition)
The shell (epithelium) that covers the capsule 's content of Sealmess capsule of the present invention is by comprising gelatin and plasticizer and being substantially free of the interfacial tension conditioning agent or the shell composition of gelation promoter forms.
" gelatin " described herein is, for example, is generally used for preparing the gelatin of Sealmess capsule, such as the pharmagel of stipulating among the JapanesePharmacopoeia Fifteenth Edition. The concept of the gelatin of this paper comprises, for example, and the gelatin of modification such as Succinylated gelatin etc.
Particularly, be preferred for implementing gelatin of the present invention and comprise those with following character.
1) gel strength of gelatin (based on the method test of describing among the JIS) is 200-300g, preferred 240-300g, more preferably 240-280g.
2) viscosity of gelatin (based on the method test of describing among the JIS) is 2-6mPas, preferred 3-6mPas, more preferably 3-5mPas.
3) described gelatin is from pigskin.
For preparing Sealmess capsule of the present invention, one or more gelatin capable of being combined. In this case, mix gelatin and preferably have above-mentioned 1) gel strength and/or above-mentioned 2) gelatin viscosity.
Most preferably satisfy the material of one or more above-mentioned conditions.
As " plasticizer " herein, can mention those that are generally used for preparing Sealmess capsule, for example, polyalcohol such as glycerine, ethylene glycol, polyethylene glycol, propane diols, polypropylene glycol etc., or preferred sugar alcohol such as sorbierite etc. These plasticizer use with a kind of use or multiple combination.
Among these, be preferred for implementing be glycerine and sorbierite of the present invention.
Also preferably use the two mixture. In this case, for implementing the present invention, the weight ratio of glycerine and sorbierite is preferably 1: 5-5: in 1 the scope, be particularly preferably 1: 3-3: 1 scope.
For implementing the present invention, the gelatin that this shell composition preferably comprises and the weight ratio scope of plasticizer are 10: 1-1: 10, be particularly preferably 10: 1-1: 1.
(capsule 's content)
The content that is encapsulated in the Sealmess capsule of the present invention is not particularly limited, as long as it does not contain interfacial tension conditioning agent or gelation promoter. As content, use required material according to purpose. For example, can mention active constituents of medicine, food, spices, seed, microorganism, plant cell, plant tissue, zooblast, animal tissue's (hereinafter referred to as main component) etc. This capsule 's content can be independent main component or is the composition that comprises main component and other additive. The content of main component in the Sealmess capsule, and the kind of additive and content etc. can be determined suitably according to its application target. The present invention is hereinafter by being explained in more detail " active constituents of medicine " example as capsule 's content.
The active constituents of medicine that is included in the Sealmess capsule is not particularly limited, and preferably has the compound of easy oxidation characteristic and the compound of oily.
An example of this active constituents of medicine is omega 3-fatty acid Arrcostab (for example, omega 3-fatty acid C1-6Arrcostab; Preferred omega 3-fatty acid ethyl ester). In this article, the example of " omega 3-fatty acid " of omega 3-fatty acid Arrcostab comprises C18-22Omega 3-fatty acid (for example, octatecatrienoic acid, parinaric acid, eicosatetraenoic acid, eicosapentaenoic acid, 21 carbon 5 alkene acids, clupanodonic acid, DHA).
The instantiation of omega 3-fatty acid ethyl ester comprises the octatecatrienoic acid ethyl ester, the stearidonic acetoacetic ester, the Eicosatetraenoic acetoacetic ester, eicosapentaenoic acid (EPA) ethyl ester, 21 carbon 5 alkene acid ethyl esters, the clupanodonic acid ethyl ester, DHA (DHA) ethyl ester, and they two or more mixture (for example, Ω in the European Pharmacopoeia-3-acetoacetic ester 90, it is used for the treatment of hyperlipidemia (for example, hypercholesterolemia, height-LDL-C mass formed by blood stasis, low-the HDL cholesterolemia, high triglyceride (TG) mass formed by blood stasis) etc., angiocardiopathy preventing, etc.).
When active constituents of medicine was encapsulated in the Sealmess capsule, its form with " active constituents of medicine composition " was encapsulated. In this article, be somebody's turn to do the mixture that " active constituents of medicine composition " comprises independent active constituents of medicine and the normally used additive of active constituents of medicine and drug products field.
The example of above-mentioned concrete active constituents of medicine composition is
1) comprises and be not less than 90%w/w (for example, 90-100%w/w) the composition of omega 3-fatty acid Arrcostab;
2) composition above-mentioned 1), its comprise be not less than 90%w/w (for example, omega 3-fatty acid Arrcostab 90-100%w/w), wherein EPA-EE and/or DHA-EE are main component;
3) composition above-mentioned 2), total containing ratio of the EPA-EE that it comprises and two kinds of compositions of DHA-EE is not less than 80%w/w (for example, 80-100%w/w; Preferred 80-90%w/w) (herein, said composition also can comprise other omega 3-fatty acid Arrcostab except containing EPA-EE and DHA-EE);
4) composition above-mentioned 3), it comprises and is not less than 40%w/w (for example, 40-66%w/w; Preferred 40-50%w/w) EPA-EE and be not less than 34%w/w (for example, 34-60%w/w; Preferred 34-45%w/w) DHA-EE, wherein total containing ratio of EPA-EE and DHA-EE is not less than 80%w/w (said composition also can comprise other omega 3-fatty acid Arrcostab except containing EPA-EE and DHA-EE) herein;
5) composition above-mentioned 4), it is the Ω-3-acetoacetic ester 90 in the European Pharmacopoeia;
Above-mentioned %w/w is the containing ratio of the gross weight of the relative capsule 's content of active constituents of medicine.
Said medicine active ingredient compositions 1)-5) can be consisted of by independent omega 3-fatty acid Arrcostab (it is active constituents of medicine), or can further comprise additive except described active constituents of medicine.
As this additive, can mention following those, wherein preferred stabilizer (preferably, alpha-tocopherol). In the time will using stabilizing agent, its content in the active constituents of medicine composition is 0.3-0.5%w/w.
This active constituents of medicine composition can solution, emulsion, suspension or other liquid form be for the preparation of Sealmess capsule. When this active constituents of medicine this during as liquid, but its also former state use.
In this article, the weight ratio of the weight of active constituents of medicine composition and " gross weight of gelatin and plasticizer " is generally 10: 1-1: 10, preferred 10: 1-1: 3.
The ratio of the weight of shell and the weight of capsule 's content is generally 10: 1-1: 10, preferred 3: 1-1: 10.
(interfacial tension conditioning agent and gelation promoter)
Sealmess capsule of the present invention is formed by shell and capsule 's content.
In Sealmess capsule of the present invention, being characterized as of shell composition do not contain usually widely used in the preparation of Sealmess capsule " interfacial tension conditioning agent " and " gelation promoter ". Owing in Sealmess capsule, do not have these compositions, can avoid defective of the prior art. Capsule 's content does not contain " interfacial tension conditioning agent " and " gelation promoter " equally. Owing to do not have these compositions, can avoid defective of the prior art yet
In this article, be somebody's turn to do the material that " interfacial tension conditioning agent " refers to change the tension force that oil-water interface produces between capsule 's content and the shell composition solution. The example comprises phosphatide, the grease class, and surfactant, polar organic solvent such as alcohol etc., etc.
In this article, be somebody's turn to do the material that " gelation promoter " refers to the cooling gelatine of shell composition solution is had facilitation. The example comprises polar organic solvent such as alcohol etc., polysaccharide etc.
In this article, do not refer to as " not containing interfacial tension conditioning agent or gelation promoter "
1) in Sealmess capsule, do not contain these two kinds of compositions fully, or
2) even when these two kinds of compositions or arbitrary composition are included in the Sealmess capsule, its content " is not enough to significantly change interfacial tension " or " is not enough to significantly shorten gelling time.
The amount that " significantly changes interfacial tension " herein is, for example, when measuring aqueous gelatin solution (21.25%w/w, 50 ℃) and content liquid (24 ℃) between oil-water interface produce tension force the time, than not adding " interfacial tension conditioning agent ", cause the amount of the variation that is not less than 5mN/m, or cause the amount that is not less than 10% variation. This interfacial tension is passed through, and for example, uses First Ten Angstroms, and the sessile drop method of the FTA200 of Inc (pendant drop) is measured.
" significantly shortening the amount of gelling time " is, for example, aspect the necessary time of the gelation when in 4 ℃ miglyol 812, being heated to 55 ℃ aqueous gelatin solution (21.25%w/w), namely, reach 50% level of the elastic force of aqueous gelatin solution in the time of 4 ℃ aspect the required time, than not adding " gelation promoter ", shorten 10% the amount that is not less than.
In other words, " not containing interfacial tension conditioning agent or gelation promoter " refers to not exist " interfacial tension conditioning agent " and does not also have " gelation promoter " (comprise and be substantially free of (that is, basically not existing)). In this article, " basically do not exist " the interfacial tension conditioning agent to refer to exist the interfacial tension conditioning agent of " amount that is not enough to significantly change interfacial tension ", and " basically not existing " gelation promoter refer to exist the gelation promoter of " amount that is not enough to significantly shorten gelling time ".
Therefore, " do not contain interfacial tension conditioning agent or gelation promoter " and comprise following embodiment:
1) Sealmess capsule of the present invention does not contain the interfacial tension conditioning agent fully and does not contain gelation promoter fully;
2-1) Sealmess capsule of the present invention is substantially free of the interfacial tension conditioning agent and is substantially free of gelation promoter;
2-2) Sealmess capsule of the present invention is substantially free of the interfacial tension conditioning agent and does not contain gelation promoter fully; With
2-3) Sealmess capsule of the present invention does not contain the interfacial tension conditioning agent fully and is substantially free of gelation promoter.
Sealmess capsule of the present invention can comprise the composition except " interfacial tension conditioning agent " and " gelation promoter " when needed, for example, can comprise colouring agent. The colouring agent that is included in the composition is not particularly limited, and uses on demand required colouring agent. For example, can mention the yellow No.5 of food coloring such as pigment, color red No.2, the blue No.2 of pigment etc.; Bata-carotene; Food color lake pigment; Di-iron trioxide, iron oxide yellow; Deng.
And when needed, Sealmess capsule of the present invention can comprise following composition, such as monose (for example, pentose such as arabinose, wood sugar, ribose, 2-deoxyribosyl etc.; Hexose such as glucose, fructose, galactolipin, mannose, sorbose, rhamnose, fucose etc.), disaccharides is (for example, maltose, cellobiose, α, α-trehalose, lactose, sucrose), cellulose (for example, avicel cellulose (comprising microcrystalline cellulose)), inorganic product is (for example, anhydrous calcium phosphate, winnofil, calcium silicates) etc.
When above-mentioned arbitrary composition has the effect that changes interfacial tension and/or shortens time spent of doing of gelling time, Sealmess capsule of the present invention can comprise and is not enough to the composition with this effect that significantly changes the amount of interfacial tension and be not enough to significantly shorten the amount of gelling time.
Sealmess capsule of the present invention also can further comprise the normally used additive in drug products field except comprising the mentioned component. The example of this additive comprises the diluent (for example, medium chain triglyceride (MCT) oil, olive oil, soybean oil, corn oil, water, ethanol, its mixture) of non-activity; PH adjusting agent (for example, citrate, phosphate, carbonate, tartrate, fumarate, acetate, amino-acid salt); Surfactant (for example, NaLS, polyoxyethylene sorbitan monoleate, polyethylene glycol (160) polypropylene glycol (30)); Stabilizing agent (for example, alpha-tocopherol, sodium ethylene diamine tetracetate (sodiumtetraedetate), acid amides nicotinic acid, cyclodextrin); Acid (for example, ascorbic acid, citric acid, tartaric acid, malic acid); Spices (for example, menthol, peppermint oil, lemon oil, vanillic aldehyde, blueberry spices); Fluidizing reagent (for example, light anhydrous silicic acid, hydrated SiO 2, talcum); Deng.
When above-mentioned arbitrary additive has the effect that changes interfacial tension and/or shortens time spent of doing of gelling time, Sealmess capsule of the present invention can comprise and is not enough to the additive with this effect that significantly changes the amount of interfacial tension and be not enough to significantly shorten the amount of gelling time.
Each composition of above-mentioned shell composition is that for example, mixed dissolution is in aqueous medium and for the preparation of Sealmess capsule (being called " shell composition solution ").
The concentration (constituent concentration) of composition is preferably 15-35%w/w beyond the water of " shell composition solution ".When using the low viscosity gelatin, can increase constituent concentration, the result can shorten the drying time after the Sealmess capsule preparation.In this article, described low viscosity is meant 2-4mPas.
(carrier fluid)
For preparing Sealmess capsule of the present invention, can use this field normally used " carrier fluid " (for example, MCT oil, etc.).
The example of this area normally used " carrier fluid " comprises oleaginous base such as MCT Oil (MCT) oil, olive oil, soybean oil, corn wet goods.
(preparation of Sealmess capsule)
Sealmess capsule of the present invention is by following preparation, use above-mentioned " shell composition solution " and " capsule 's content ", with the capsule preparation facilities that is generally used for preparing Sealmess capsule (for example, " SPHEREX " that FreundCorporation produces), use is used for the multiple nozzle of two kinds of compositions, by dropping preparation method preparation in the liquid.
More particularly, capsule 's content flows out and the shell composition solution flows out from the outside nozzle of multiple nozzle and enters carrier fluid with given pace respectively from the inboard nozzle of multiple nozzle, this two-layer liquid stream cuts off with predetermined distance, owing to interfacial tension forms drop, gelatine obtains Sealmess capsule to Wai Ce shell by cooling then.With gained Sealmess capsule cooling official hour, drying obtains goods then.
Yet the preparation of Sealmess capsule of the present invention is not limited to this preparation method, also can be by known other method preparation in this field.
The size of Sealmess capsule of the present invention can suitably be regulated by known method.Preferred diameter is the capsule of 1-10mm scope, and more preferably diameter is the capsule of 2-6mm scope.
When preparing the Sealmess capsule of invention, preferably in preparation process, control the temperature conditions that capsule forms near point (the multiple nozzle) suitably.
When near the interfacial tension of the temperature of main constituent 25 ℃ that capsule 's content contains is compared with suitable interfacial tension, when showing low or too high interfacial tension, (especially when the content of the main component that showed low or too high interfacial tension in the capsule 's content is high), suitable control temperature is being especially preferred aspect the preparation high-quality Sealmess capsule.
In the present invention, suitable interfacial tension is, for example, with the interface of aqueous gelatin solution (21.25%w/w, 50 ℃) in be 15-50mN/m.The interfacial tension that is lower than this level can be categorized as " low excessively ", and the interfacial tension that is higher than this level can be categorized as " too high ".This interfacial tension can be measured by for example said method.In addition, this numerical value is an index, and it can change at zone of reasonableness by capsule 's content used according to the invention.Those skilled in the art can optionally consider temperature controlled necessity according to implementing concrete situation of the present invention.
In preferred embodiments, keep following condition to prepare Sealmess capsule, wherein, near the multiple nozzle of Sealmess capsule preparation facilities,
1-1) temperature of " capsule 's content " is controlled between the setting value (value set) ± 2 ℃, and this temperature is in 5-25 ℃ of scope;
2-1) temperature of " shell composition solution " is controlled between setting value ± 2 ℃, and this temperature is in 50-80 ℃ of scope;
3-1) temperature of " carrier fluid " is controlled between setting value ± 1 ℃, and this temperature is in 1-15 ℃ of scope;
4-1) difference of the temperature of the temperature of " capsule 's content " and " shell composition solution " is not less than 25 ℃ and be not more than 75 ℃; With
5-1) difference of the temperature of the temperature of " shell composition solution " and " carrier fluid " is not less than 35 ℃ and be not more than 79 ℃.
Can under the said temperature condition, obtain to have enough high-quality Sealmess capsule.For preparation has higher-quality Sealmess capsule, keeping following condition to prepare Sealmess capsule, wherein
1-2) temperature of " capsule 's content " is controlled between setting value ± 2 ℃ (preferred ± 1 ℃), and this temperature is in 12-22 ℃ of scope;
2-2) temperature of " shell composition solution " is controlled between setting value ± 2 ℃ (preferred ± 1 ℃), and this temperature is in 60-70 ℃ of scope;
3-2) temperature of " carrier fluid " is controlled between setting value ± 1 ℃ (preferred ± 0.5 ℃), and this temperature is 3-11 ℃ of scope;
4-2) difference of the temperature of the temperature of " capsule 's content " and " shell composition solution " is not less than 38 ℃ and be not more than 58 ℃; With
5-2) difference of the temperature of the temperature of " shell composition solution " and " carrier fluid " is not less than 49 ℃ and be not more than 67 ℃.
The said temperature condition can be determined by those skilled in the art suitably according to the required quality level of Sealmess capsule.
When preparation Sealmess capsule of the present invention, particularly advantageously be to satisfy all above-mentioned condition 1-1) to 5-1).
Said temperature control can be easy to be undertaken by for example making up PID control and feedback control by those skilled in the art, but this control method is not limited thereto.
Sealmess capsule of the present invention has by containing gelatin and plasticizer but does not contain the interfacial tension regulator or shell that the shell compositions of gelation promoter (do not comprise the interfacial tension regulator and do not comprise gelation promoter) forms.Sealmess capsule of the present invention does not preferably contain interfacial tension regulator or gelation promoter (do not comprise the interfacial tension regulator and do not comprise gelation promoter) yet in its capsule 's content, and just encapsulated back (in encapsulated back and before dry), the minimum/maximum ratio of a capsular thickness of the shell is not less than 0.6.That is, novel Sealmess capsule, its mesochite does not contain interfacial tension regulator and gelation promoter, and preferably capsule 's content does not contain these compositions yet, and thickness shows minimum inhomogeneities.
Particularly, the level of the uneven gauge of Sealmess capsule of the present invention, when just encapsulated back was by microexamination, the minimum/high specific of dry preceding thickness of the shell was not less than 0.6, more preferably is not less than 0.8, also more preferably is not less than 0.9.This thickness can be measured by general image analysis method.When there is following shortcoming in the minimum/high specific of thickness of the shell less than 0.6 the time, uneven gauge increases, and this shell breaks in dry and dried storage process, and the capsule 's content leakage.
In addition, because shell evenly contraction in dry run, even the thickness of the shell minimum/high specific before dry also keeps after drying.
In addition, Sealmess capsule of the present invention has by containing gelatin and plasticizer but does not contain the interfacial tension regulator or shell that the shell compositions of gelation promoter forms.Preferably, capsule 's content does not contain interfacial tension regulator or gelation promoter yet, and does not have bubble eye, even or exist and only have minimum bubble eye yet.When bubble eye exists, by in encapsulated back and microexamination before dry just, the diameter of bubble be not more than dry fore shell average thickness ((maximum+minimum)/2) 1/2, more preferably no more than 1/4, also more preferably no more than 1/8.Especially, the present invention is the Sealmess capsule with shell, described shell is by containing gelatin and plasticizer but do not contain the interfacial tension regulator or the shell compositions of gelation promoter (do not contain the interfacial tension regulator and do not contain gelation promoter) forms, when before encapsulated back and drying, measuring, it does not contain 1/2 the bubble eye that diameter surpasses the average thickness of shell, is preferably the Sealmess capsule with the capsule 's content that does not contain interfacial tension regulator or gelation promoter (do not contain the interfacial tension regulator and do not contain gelation promoter).When the diameter of described bubble eye surpasses 1/2 ((maximum+minimum)/2) of average thickness of shell, in shell, produce defective such as crack at dry and dried storage process, and the leakage of generation capsule 's content.
In this article, the bubble eye is meant the spherical cavity shape defective that produces in the shell, can comprise capsule 's content in the described cavity.Described bubble eye is generally the little spheroid of distortion, but it can be the spheroid of distortion.In non-true spheric bulb eye, described " bubble eye diameter " is meant the diameter on maximum direction.Sealmess capsule can have a plurality of bubble eyes, and each diameter is in above-mentioned scope.Thickness and bubble eye diameter can be by measuring as the image analysis method in the measurement of uneven gauge.
In this manual, in shell, exist diameter be shell average thickness 1/2 or littler bubble at the moment, this shell can be expressed as does not sometimes have " bubble eye ".
But of the present invention comprise active constituents of medicine as the Sealmess capsule safe administration of its content in mammal (for example, mice, rat, rabbit, cat, Canis familiaris L., cattle, horse, monkey, people).
In this embodiment, the dosage of Sealmess capsule of the present invention gets final product for the effective dose of each active constituents of medicine of comprising in capsule.Sealmess capsule of the present invention changes to the characteristic of above-mentioned mammiferous administration frequency according to the active constituents of medicine that comprises in one day, and representational is one day 1-3 time.
As instantiation, the effective dose of Ω-3-acetoacetic ester 90 is 100-6000mg/ days for adult (body weight 60kg).
The instantiation of the particularly preferred Sealmess capsule of the present invention comprises following:
1) Sealmess capsule, it comprises gelatin, and comprises glycerol and sorbitol as plasticizer, and each capsule comprises 25mg Ω-3-acetoacetic ester 90 as capsule 's content;
2) Sealmess capsule, it comprises gelatin, and comprises glycerol and sorbitol as plasticizer, and each capsule comprises 50mg Ω-3-acetoacetic ester 90 as capsule 's content;
3) Sealmess capsule, it comprises gelatin, and comprises glycerol and sorbitol as plasticizer, and each capsule comprises 100mg Ω-3-acetoacetic ester 90 as capsule 's content;
4) Sealmess capsule, it comprises gelatin, and comprises glycerol and sorbitol as plasticizer, and each capsule comprises 200mg Ω-3-acetoacetic ester 90 as capsule 's content.
Embodiment
The present invention explains in following examples and experimental example in more detail, but it is not construed as limiting the invention.
The various gelatin that use in following examples are commercially available, even or they be not commercially available, they also can be made and easily obtained by gelatin manufacturer.
As formulation additives, use those that list among Japanese Pharmacopoeia Fifteenth Edition, Japanese Pharmacopoeia Pharmaceutical Codex or the Pharmaceutical Excipients2003.
Embodiment 1
With gelatin 1 (gel strength 245g, viscosity 4.3mPas, 3158g), gelatin 2 (gel strength 297g, viscosity 5.3mPas, 1579g), concentrated glycerin (concentrated glycerin) (559.0g), sorbitol solution (399.2g, solid constituent: 299.4g) be added in the Purified Water (16610g) that is heated to 52 ℃ with the yellow No.5 of pigment (1.17g).With the mixture dissolving, and the degassing (shell composition solution) under reduced pressure.Proportion of composing with Ω-3-acetoacetic ester 90 during as 1000.00 weight portions is shown in table 1.
Sealmess capsule preparation facilities (SPHEREX is by Freund Corporation preparation) is used to prepare Sealmess capsule.Near the temperature of " Ω-3-acetoacetic ester 90 " (capsule 's content) nozzle is controlled at 16.3-18.9 ℃, the shell aqueous solution is controlled at 67.8-68.3 ℃, MCT oil (it is as carrier fluid) is controlled at 5.9-7.1 ℃, and carries out encapsulated with 25 capsular speed of per second.
This encapsulation step can be controlled temperature by strictness and operate continually and steadily.
The gained capsule is at refrigerator and cooled but (5 ℃, 14 hours), and dryly in drying machine reaches below 0.2 up to water activity.Carrier fluid on the capsule surface is wiped to obtain the Sealmess capsule that each capsule contains 25mg Ω-3-acetoacetic ester 90 then.
The central value of the capsular size of gained is about 4mm φ (changing in the scope of 3.5-4.5mm φ).
[table 1]
Embodiment 2
With gelatin 3 (gel strength 255g, viscosity 3.5mPas, 5096.7g), concentrated glycerin (601.4g), sorbitol solution (429.2g, solid constituent: 300.4g) and the yellow No.5 of pigment (1.26g) be added in the Purified Water (13999.9g) that is heated to 55 ℃.With the mixture dissolving, and the degassing (shell composition solution) under reduced pressure.Proportion of composing with Ω-3-acetoacetic ester 90 during as 1000.00 weight portions is shown in table 2.
Sealmess capsule preparation facilities (SPHEREX is by Freund Corporation preparation) is used to prepare Sealmess capsule.Near the temperature of " Ω-3-acetoacetic ester 90 " (capsule 's content) nozzle is controlled at 16.3-16.7 ℃, and the shell aqueous solution is controlled at 70.3-70.4 ℃.MCT oil is controlled at 6.8-7.1 ℃ as carrier fluid and its temperature, and carries out encapsulated with 25 capsular speed of per second.
This encapsulation step can be controlled temperature by strictness and operate continually and steadily.
The gained capsule is at refrigerator and cooled but (4 ℃, 28 hours), and dryly in drying machine reaches below 0.2 up to water activity.Carrier fluid on the capsule surface is wiped to obtain the Sealmess capsule that each capsule contains 25mg Ω-3-acetoacetic ester 90 then.
The central value of the capsular size of gained is about 4mm φ (changing in the scope of 3.5-4.5mm φ).
[table 2]
Embodiment 3
With gelatin 1 (gel strength 245g, viscosity 4.3mPas, 3158g), gelatin 2 (gel strength 297g, viscosity 5.3mPas, 1579g), concentrated glycerin (559.0g), sorbitol solution (399.2g, solid constituent: 299.4g) be added in the Purified Water (16610g) that is heated to 52 ℃ with the yellow No.5 of pigment (1.17g).With the mixture dissolving, and the degassing (shell composition solution) under reduced pressure.Proportion of composing with Ω-3-acetoacetic ester 90 during as 1000.00 weight portions is shown in table 3.
Sealmess capsule preparation facilities (SPHEREX is by Freund Corporation preparation) is used to prepare Sealmess capsule.Near the temperature of " Ω-3-acetoacetic ester 90 " (capsule 's content) nozzle is controlled at 17.7-18.8 ℃, and the shell aqueous solution is controlled at 67.5-68.1 ℃.MCT oil is controlled at 6.4-6.8 ℃ as carrier fluid and its temperature, and carries out encapsulated with 25 capsular speed of per second.
This encapsulation step can be controlled temperature by strictness and operate continually and steadily.
The gained capsule is at refrigerator and cooled but (5 ℃, 14 hours), and dryly in drying machine reaches below 0.2 up to water activity.Carrier fluid on the capsule surface is wiped to obtain the Sealmess capsule that each capsule contains 25mg Ω-3-acetoacetic ester 90 then.
The central value of the capsular size of gained is about 4mm φ (changing in the scope of 3.5-4.5mm φ).
[table 3]
Embodiment 4
With gelatin 4 (gel strength 264g, viscosity 4.2mPas, 3398g), concentrated glycerin (401g), sorbitol solution (286g, solid constituent: 200.2g) and the yellow No.5 of pigment (0.84g) be added into the Purified Water (15914g) that is heated to 55 ℃.With the mixture dissolving, and the degassing (shell composition solution) under reduced pressure.Proportion of composing with Ω-3-acetoacetic ester 90 during as 1000.00 weight portions is shown in table 4.
Sealmess capsule preparation facilities (SPHEREX is by Freund Corporation preparation) is used to prepare Sealmess capsule.Near the temperature of " Ω-3-acetoacetic ester 90 " (capsule 's content) nozzle is controlled at 14.7 ℃, and the shell aqueous solution is controlled at 56.7 ℃.MCT oil is controlled at 4.4 ℃ as carrier fluid and its temperature, and carries out encapsulated with 7 capsular speed of per second.
This encapsulation step can be controlled temperature by strictness and operate continually and steadily.
The gained capsule is at refrigerator and cooled but (4 ℃, 21 hours), and dryly in drying machine reaches below 0.2 up to water activity.Carrier fluid on the capsule surface is wiped to obtain the Sealmess capsule that each capsule contains 200mg Ω-3-acetoacetic ester 90 then.
The central value of the capsular size of gained is about 8mm φ (changing in the scope of 7.5-8.5mm φ).
[table 4]
Embodiment 5
With gelatin 4 (gel strength 264g, viscosity 4.2mPas, 9568.125g), concentrated glycerin (1128.75g) and sorbitol solution (806.1g, solid constituent: 564.3g) be added into the Purified Water (33541.5g) that is heated to 55 ℃.With the mixture dissolving, and the degassing (shell composition solution) under reduced pressure.Proportion of composing with Ω-3-acetoacetic ester 90 during as 1000.00 weight portions is shown in table 5.
Sealmess capsule preparation facilities (by Fuji Capsule Co., the Ltd. preparation) is used to prepare Sealmess capsule.Near the temperature of " Ω-3-acetoacetic ester 90 " (capsule 's content) nozzle is controlled at 22.8-23.2 ℃, and the shell aqueous solution is controlled at 69.9-70.3 ℃.MCT oil is controlled at 6.4-6.7 ℃ as carrier fluid and its temperature, and carries out encapsulated with 25 capsular speed of per second.
This encapsulation step can be controlled temperature by strictness and operate continually and steadily.
The gained capsule is at refrigerator and cooled but (5 ℃, 15 hours), and dryly in drying machine reaches below 0.2 up to water activity.Carrier fluid on the capsule surface is wiped to obtain the Sealmess capsule that each capsule contains 25mg Ω-3-acetoacetic ester 90 then.
The central value of the capsular size of gained is about 4mm φ (changing in the scope of 3.5-4.5mm φ).
[table 5]
Embodiment 6
The Sealmess capsule that uses embodiment 5 to obtain, the Sealmess capsule of preparation aromatization.Proportion of composing with Ω-3-acetoacetic ester 90 during as 1000.00 weight portions is shown in table 6.
Ethanol (22.4g) and blue berry spice (blueberry flavor) (5.6g) are mixed to obtain fragrant liquid.Use rotary drum coating machine (HICOATER: by Freund Corporation preparation) that fragrant liquid (every 300g Sealmess capsule is 1.47g) is interspersed among on the Sealmess capsule that embodiment 5 obtains with they aromatizations.Behind the aromatization, the ethanol in use rotary drum coating machine (HICOATER: by Freund Corporation preparation) the removal Sealmess capsule reaches up to it and is not more than 5000ppm, obtains the Sealmess capsule of aromatization.
[table 6]
Embodiment 7
With gelatin 1 (gel strength 245g, viscosity 4.3mPas, 3158g), gelatin 2 (gel strength 297g, viscosity 5.3mPas, 1579g), concentrated glycerin (559.0g), sorbitol solution (399.2g, solid constituent: 299.4g) be added in the Purified Water (16610g) that is heated to 52 ℃ with the yellow No.5 of pigment (1.17g).With the mixture dissolving, and the degassing (shell composition solution) under reduced pressure.Proportion of composing with Ω-3-acetoacetic ester 90 during as 1000.00 weight portions is shown in table 7.
Sealmess capsule preparation facilities (SPHEREX is by Freund Corporation preparation) is used to prepare Sealmess capsule.Near the temperature of " Ω-3-acetoacetic ester 90 " (capsule 's content) nozzle is controlled at 17.7-18.8 ℃, and the shell aqueous solution is controlled at 67.5-68.1 ℃.MCT oil is controlled at 6.4-6.8 ℃ as carrier fluid and its temperature, and carries out encapsulated with 25 capsular speed of per second.
This encapsulation step can be controlled temperature by strictness and operate continually and steadily.
The gained capsule is at refrigerator and cooled but (5 ℃, 21 hours), and dryly in drying machine reaches below 0.2 up to water activity.Carrier fluid on the capsule surface is wiped to obtain the Sealmess capsule that each capsule contains 25mg Ω-3-acetoacetic ester 90 then.
With operation triplicate so far, and use rotary drum dryer (tumbler drier) (by Freund Corporation preparation) to mix the gained Sealmess capsule.Ethanol (224g) and blue berry spice (56g) are mixed with fragrant liquid.Use rotary drum dryer (by Freund Corporation preparation) that fragrant liquid (every 40655g Sealmess capsule is 199.1g) is interspersed among on the blended Sealmess capsule with they aromatizations.Behind the aromatization, the ethanol in use rotary drum dryer (by Freund Corporation preparation) the removal Sealmess capsule reaches up to it and is not more than 5000ppm, obtains the Sealmess capsule of aromatization.
The central value of the capsular size of gained is about 4mm φ (changing in the scope of 3.5-4.5mm φ).
[table 7]
The Ω that uses among the embodiment 1-7-3-acetoacetic ester 90 meets European Pharmacopoeia.Its quality is shown in table 8.
[table 8]
* containing ratio in the table and content are represented the value in the capsule 's content (active constituents of medicine compositions).
Experimental example 1
The Sealmess capsule (200g) that embodiment 3 obtains is assessed by image-type particle size distribution device (Digital Image Processing Particle Size Analyzer) (Camsizer, by Horiba, Ltd. prepares).Aspect ratio (aspect ratio) is not less than 0.95, confirms that they almost are spheric.
Experimental example 2
In embodiment 3, as content, Ω-3-acetoacetic ester 90 can reach 100% high-load.In addition, by using digital microscope (VHX-200, KEYENCE CORPORATION) capsule before dry is assessed, as shown in Figure 1, not observing the bubble eye (obtains thus to draw a conclusion, do not exist size to surpass 1/2 bubble eye of the average thickness of shell), and realized carrying out encapsulated with the few good shell of uneven gauge.The thickness of shell is 0.84mm and the minimum 0.82mm of being (minimum/as to be 0.98 to the maximum) to the maximum.
Commercial Application
The excellent in stability of the capsule 's content of Sealmess capsule of the present invention, and can comprise a large amount of capsule 's contents. And, not containing the bubble eye or have the high-quality Sealmess capsule that minimum bubble eye is also only arranged even the invention provides, its thickness shows minimum inhomogeneities. Because content can be very high, the unit sizes of preparation can diminish, thereby can realize highly being easy to utilizing in administration and the storage process littler space. And, can improve the stability in the storage process, thus expanded service life.
The number of patent application 2007-173198 that the application submits to based on Japan, its content is incorporated herein by reference fully at this.
Claims (35)
1. Sealmess capsule, it comprises shell and capsule 's content, described shell is formed by the shell compositions, and described shell compositions contains gelatin and plasticizer and do not contain the interfacial tension regulator or gelation promoter, and described capsule 's content does not contain interfacial tension regulator or gelation promoter.
2. the Sealmess capsule of claim 1, the gel strength of wherein said gelatin is 200-300g.
3. claim 1 or 2 Sealmess capsule, the viscosity of wherein said gelatin is 2-6mPas.
4. each Sealmess capsule of claim 1-3, wherein said gelatin is from Corii Sus domestica.
5. the Sealmess capsule of claim 1, wherein this plasticizer is a glycerol.
6. the Sealmess capsule of claim 1, wherein this plasticizer is a sorbitol.
7. the Sealmess capsule of claim 1, wherein this plasticizer is the mixture of glycerol and sorbitol.
8. the Sealmess capsule of claim 7, wherein the weight ratio of glycerol and sorbitol is 1: 5-5: 1.
9. the Sealmess capsule of claim 1, wherein the weight ratio of gelatin and plasticizer is 10: 1-1: 1.
10. the Sealmess capsule of claim 1, wherein said capsule 's content is the active constituents of medicine compositions.
11. the Sealmess capsule of claim 10, wherein said capsule 's content are included in the active constituents of medicine compositions that near 25 ℃ temperature had low or too high interfacial tension.
12. the Sealmess capsule of claim 10, wherein said active constituents of medicine compositions comprises the omega 3-fatty acid Arrcostab.
13. the Sealmess capsule of claim 12, wherein said active constituents of medicine compositions comprises the omega 3-fatty acid Arrcostab of the ratio that is not less than 90%w/w.
14. the Sealmess capsule of claim 13, wherein said active constituents of medicine compositions comprise EPA ethyl ester (EPA-E) and DHA ethyl ester (docosahexaenoic acid ethyl), and the toatl proportion of these two kinds of compositions is not less than 80%w/w.
15. the Sealmess capsule of claim 14, wherein said active constituents of medicine compositions comprise the EPA ethyl ester that is not less than 40%w/w and are not less than the DHA ethyl ester of 34%w/w.
16. the Sealmess capsule of claim 15, wherein said active constituents of medicine compositions comprise the Ω-3-acetoacetic ester 90 that meets European Pharmacopoeia.
17. the Sealmess capsule of claim 10, wherein the weight ratio of active constituents of medicine compositions and " summation of gelatin and plasticizer " is 10: 1-1: 10.
18. the Sealmess capsule of claim 1, the weight ratio of its mesochite and capsule 's content are 10: 1-1: 10.
19. the method for the Sealmess capsule of preparation claim 1, this method is a dropping preparation method in the liquid, be included near the multiple nozzle of the employed device of dropping preparation method the temperature of control " capsule 's content that does not contain interfacial tension regulator or gelation promoter ", the temperature of " by containing gelatin and plasticizer and not containing the interfacial tension regulator or shell composition solution that the shell compositions of gelation promoter forms " and the temperature of " carrier fluid ".
20. the preparation method of claim 19, wherein the temperature of " capsule 's content that does not contain interfacial tension regulator or gelation promoter " is controlled between setting value ± 2 ℃, and this temperature is in 5 ℃ of-25 ℃ of scopes.
21. the preparation method of claim 19, wherein the temperature of " by containing gelatin and plasticizer and not containing the interfacial tension regulator or shell composition solution that the shell compositions of gelation promoter forms " is controlled between setting value ± 2 ℃, and this temperature is in 50 ℃ of-80 ℃ of scopes.
22. the method for claim 19, wherein the temperature of " carrier fluid " is controlled between setting value ± 1 ℃, and this temperature is in 1 ℃ of-15 ℃ of scope.
23. the preparation method of claim 19, wherein the difference of the temperature of the temperature of " capsule 's content that does not contain interfacial tension regulator or gelation promoter " and " by containing gelatin and plasticizer and not containing the interfacial tension regulator or shell composition solution that the shell compositions of gelation promoter forms " is more than 25 ℃ and below 75 ℃.
24. the preparation method of claim 19, wherein the difference of the temperature of the temperature of " by containing gelatin and plasticizer and not containing the interfacial tension regulator or shell composition solution that the shell compositions of gelation promoter forms " and " carrier fluid " is more than 35 ℃ and below 79 ℃.
25. Sealmess capsule, it is by dropping preparation method preparation in the liquid, this method is included near the multiple nozzle of the employed device of dropping preparation method, the temperature of control " capsule 's content that does not contain interfacial tension regulator or gelation promoter ", the temperature of " by containing gelatin and plasticizer and not containing the interfacial tension regulator or shell composition solution that the shell compositions of gelation promoter forms " and the temperature of " carrier fluid ".
26. the Sealmess capsule of claim 25, wherein said temperature is controlled at following temperature:
The temperature of " capsule 's content " is controlled between setting value ± 2 ℃, and this temperature is in 5 ℃ of-25 ℃ of scopes;
The temperature of " shell composition solution " is controlled between setting value ± 2 ℃, and this temperature is in 50 ℃ of-80 ℃ of scopes;
The temperature of " carrier fluid " is controlled between setting value ± 1 ℃, and this temperature is 1 ℃ of-15 ℃ of scope;
The difference of the temperature of the temperature of " capsule 's content " and " shell composition solution " is more than 25 ℃ and below 75 ℃; With
The difference of the temperature of " shell composition solution " and the temperature of " carrier fluid " is more than 35 ℃ and below 79 ℃.
27. the Sealmess capsule of claim 25, wherein said temperature is controlled at following temperature:
The temperature of " capsule 's content " be controlled between setting value ± 1 ℃ and this temperature in 12 ℃ of-22 ℃ of scopes;
The temperature of " shell composition solution " is controlled between setting value ± 1 ℃, and this temperature is in 60 ℃ of-70 ℃ of scopes;
The temperature of " carrier fluid " is controlled between setting value ± 0.5 ℃, and this temperature is in 3 ℃ of-11 ℃ of scopes;
The difference of the temperature of the temperature of " capsule 's content " and " shell composition solution " is more than 38 ℃ and below 58 ℃; With
The difference of the temperature of " shell composition solution " and the temperature of " carrier fluid " is more than 49 ℃ and below 67 ℃.
28. Sealmess capsule, it has the shell that is formed by the shell compositions, and this shell compositions contains gelatin and plasticizer and do not contain the interfacial tension regulator or gelation promoter, and the ratio of the minimum thickness/maximum ga(u)ge of described shell is more than 0.6.
29. the Sealmess capsule of claim 28, it has the capsule 's content that does not contain interfacial tension regulator or gelation promoter.
30. Sealmess capsule, it has the shell that is formed by the shell compositions, and this shell compositions contains gelatin and plasticizer and do not contain the interfacial tension regulator or gelation promoter, does not have the bubble eye in the described shell.
31. the Sealmess capsule of claim 30, it has the capsule 's content that does not contain interfacial tension regulator or gelation promoter.
32. Sealmess capsule, it has the shell that is formed by the shell compositions, this shell compositions contains gelatin and plasticizer and does not contain the interfacial tension regulator or gelation promoter, in encapsulated back and before drying, the diameter of the bubble eye of shell is below 1/2 of average thickness of shell.
33. the Sealmess capsule of claim 32, it has the capsule 's content that does not contain interfacial tension regulator or gelation promoter.
34. Sealmess capsule, it has the shell that is formed by the shell compositions, this shell compositions contains gelatin and plasticizer and does not contain the interfacial tension regulator or gelation promoter, in encapsulated back and before drying, does not exist diameter to surpass 1/2 bubble eye of the average thickness of shell in the shell.
35. the Sealmess capsule of claim 34, it has the capsule 's content that does not contain interfacial tension regulator or gelation promoter.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP173198/07 | 2007-06-29 | ||
| JP2007173198 | 2007-06-29 | ||
| PCT/JP2008/061721 WO2009004999A1 (en) | 2007-06-29 | 2008-06-27 | Seamless capsule |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012100746751A Division CN102552213A (en) | 2007-06-29 | 2008-06-27 | Seamless capsule |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101801416A true CN101801416A (en) | 2010-08-11 |
| CN101801416B CN101801416B (en) | 2012-10-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008801051658A Expired - Fee Related CN101801416B (en) | 2007-06-29 | 2008-06-27 | Sealmess capsule |
| CN2012100746751A Pending CN102552213A (en) | 2007-06-29 | 2008-06-27 | Seamless capsule |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012100746751A Pending CN102552213A (en) | 2007-06-29 | 2008-06-27 | Seamless capsule |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20100119598A1 (en) |
| EP (1) | EP2172225B1 (en) |
| JP (1) | JP5047285B2 (en) |
| KR (1) | KR20100039362A (en) |
| CN (2) | CN101801416B (en) |
| AU (1) | AU2008272135B2 (en) |
| ES (1) | ES2748934T3 (en) |
| MY (1) | MY157882A (en) |
| NZ (1) | NZ582576A (en) |
| TW (1) | TW200911358A (en) |
| WO (1) | WO2009004999A1 (en) |
Cited By (1)
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|---|---|---|---|---|
| CN103957897A (en) * | 2011-09-29 | 2014-07-30 | 森下仁丹株式会社 | Seamless capsule and manufacturing method therefor |
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| JPH0412083A (en) * | 1990-04-27 | 1992-01-16 | Osaka Titanium Co Ltd | Production of silicon single crystal |
| JP3159724B2 (en) | 1991-04-19 | 2001-04-23 | フロイント産業株式会社 | Seamless capsule manufacturing method and apparatus |
| JPH0826976A (en) * | 1994-07-21 | 1996-01-30 | Freunt Ind Co Ltd | Food-like medicine |
| US5650232A (en) * | 1994-10-07 | 1997-07-22 | Warner-Lambert Company | Method for making seamless capsules |
| JP3759986B2 (en) * | 1995-12-07 | 2006-03-29 | フロイント産業株式会社 | Seamless capsule and manufacturing method thereof |
| ATE305810T1 (en) * | 2000-05-22 | 2005-10-15 | Pro Aparts Investimentos E Con | PHARMACEUTICAL COMPOSITION CONTAINING FATTY ACID WHICH IS AT LEAST 80 Wt. CONTAINS EPA AND DHA |
| EP1709958A1 (en) * | 2002-12-05 | 2006-10-11 | Symrise GmbH & Co. KG | Seamless filled capsules |
| AU2003288606A1 (en) * | 2002-12-20 | 2004-07-14 | Pronova Biocare As | Use of a fatty acid composition for treatment of male infertility |
| JP2004262774A (en) * | 2003-02-20 | 2004-09-24 | Freunt Ind Co Ltd | Seamless capsule |
| GB0403247D0 (en) * | 2004-02-13 | 2004-03-17 | Tillotts Pharma Ag | A pharmaceutical composition |
| WO2005077521A1 (en) * | 2004-02-17 | 2005-08-25 | Symrise Gmbh & Co. Kg | Coated sherical seamless filled capsules |
| US20090304784A1 (en) * | 2006-07-28 | 2009-12-10 | V. Mane Fils | Seamless capsules containing high amounts of polyunsaturated fatty acids and a flavouring component |
-
2008
- 2008-06-27 ES ES08790686T patent/ES2748934T3/en active Active
- 2008-06-27 CN CN2008801051658A patent/CN101801416B/en not_active Expired - Fee Related
- 2008-06-27 JP JP2009521608A patent/JP5047285B2/en active Active
- 2008-06-27 EP EP08790686.3A patent/EP2172225B1/en active Active
- 2008-06-27 AU AU2008272135A patent/AU2008272135B2/en not_active Expired - Fee Related
- 2008-06-27 CN CN2012100746751A patent/CN102552213A/en active Pending
- 2008-06-27 WO PCT/JP2008/061721 patent/WO2009004999A1/en active Application Filing
- 2008-06-27 KR KR1020107001925A patent/KR20100039362A/en not_active Application Discontinuation
- 2008-06-27 MY MYPI20095565A patent/MY157882A/en unknown
- 2008-06-27 TW TW097124053A patent/TW200911358A/en unknown
- 2008-06-27 US US12/452,374 patent/US20100119598A1/en not_active Abandoned
- 2008-06-27 NZ NZ582576A patent/NZ582576A/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103957897A (en) * | 2011-09-29 | 2014-07-30 | 森下仁丹株式会社 | Seamless capsule and manufacturing method therefor |
| CN108619112A (en) * | 2011-09-29 | 2018-10-09 | 森下仁丹株式会社 | Sealmess capsule and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2172225A8 (en) | 2011-06-29 |
| US20100119598A1 (en) | 2010-05-13 |
| TW200911358A (en) | 2009-03-16 |
| EP2172225B1 (en) | 2019-08-07 |
| AU2008272135B2 (en) | 2013-10-31 |
| JP5047285B2 (en) | 2012-10-10 |
| AU2008272135A1 (en) | 2009-01-08 |
| NZ582576A (en) | 2012-05-25 |
| WO2009004999A8 (en) | 2009-04-09 |
| KR20100039362A (en) | 2010-04-15 |
| CN102552213A (en) | 2012-07-11 |
| ES2748934T3 (en) | 2020-03-18 |
| MY157882A (en) | 2016-07-29 |
| EP2172225A1 (en) | 2010-04-07 |
| WO2009004999A1 (en) | 2009-01-08 |
| JPWO2009004999A1 (en) | 2010-08-26 |
| CN101801416B (en) | 2012-10-24 |
| EP2172225A4 (en) | 2011-04-27 |
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